Synthesis and evaluation of 3-alkynyl-5-aryl-7-aza-indoles as broad-spectrum antiviral agents

Abstract

RNA viral infections, including those caused by respiratory syncytial virus (RSV), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and Venezuelan Equine encephalitis virus (VEEV), pose a major global health challenge. Here, we report the synthesis and screening of a series of pyrrolo[2,3-b]pyridines targeting RSV, SARS-CoV-2 and/or VEEV. From this campaign, a series of lead compounds was generated that demonstrated antiviral activity in the low single-digit micromolar range against the various viruses and did not show cytotoxicity. These findings highlight the potential of 3-alkynyl-5-aryl-7-aza-indoles as a promising chemotype for the development of broad-spectrum antiviral agents.

Recent Progress toward the Discovery of Small Molecules as Novel Anti-Respiratory Syncytial Virus Agents

“…A pyrrolo [2,3-b]pyridine analogue (compound 79, Figure 21) was identified as a potent anti-RSV agent (EC 50 = 0.19 μM) but with a low CC 50 value (2 μM). 173 Medicinal chemistry efforts focused on functionalizing the C-5 position and the alkynyl substituent, resulting in the identification of a series of derivatives with comparable EC 50 values to the starting hit but decreased cytotoxicity. Compound 80 (Figure 21) exhibited an EC 50 of 0.16 μM and a CC 50 > 50 μM and retained its anti-RSV activity (EC 50 = 0.59 μM) also when tested on different cells (A549).…”

“…This raised doubts about the MoA of this series of pyrrolo [2,3b]pyridine analogues. 173 In the same year, da Silva et al synthesized a series of triterpene derivatives that led to the identification of compound 81 (Figure 21), which is substituted with triazole and showed better anti-RSV activity (EC 50 = 0.05 μM, CPE on A549 cells infected with RSV A2 strain) than its close triterpene analogue, ursolic acid (which is approximately 3-fold less potent). In silico studies suggested that compound 75 may target inosine monophosphate dehydrogenase.…”

“…In 2022, Martinez-Gualda et al performed a screening of an in-house library to evaluate the CPE effect on HEp-2 cells infected with RSV A Long strain. A pyrrolo­[2,3- b ]­pyridine analogue (compound 79 , Figure ) was identified as a potent anti-RSV agent (EC 50 = 0.19 μM) but with a low CC 50 value (2 μM) . Medicinal chemistry efforts focused on functionalizing the C-5 position and the alkynyl substituent, resulting in the identification of a series of derivatives with comparable EC 50 values to the starting hit but decreased cytotoxicity.…”

“…Although compound 80 showed a nanomolar affinity toward the adaptor-associated kinase 1 (AAK1), a close analogue of it, which was endowed with anti-RSV activity, did not inhibit AAK1 (IC 50 > 10 μM). This raised doubts about the MoA of this series of pyrrolo­[2,3- b ]­pyridine analogues …”